Alzheimer's disease (hereinafter, referred to as “AD”) is generally characterized by accumulation of amyloid in a senile plaque. Amyloid is mainly amyloid ρ proteins of 40 and 42 amino acid residues (hereinafter, referred to as “Aβ40” and “Aβ42”, respectively). These proteins are generated by degradation of an amyloid precursor protein (APP) by two proteases, β- and γ-secretases. In the onset of AD, Aβ42 has been considered to take a more important role than Aβ40 due to its aggregation propensity and neural toxicity. Recent study has shown that an oxidation stress contributes to neurodegenaration associated with AD. Radical forming-mediated neural toxicity of Aβ42 is closely associated with radicalization of tyrosine at position 10 and at position 35 which accompanies generation of active oxygen species. In addition, there has been an evidence that accumulation of an oligomer of Aβ induces AD through synaptic toxicity.
An Alzheimer's disease model mouse inoculated with an Aβ aggregate as a vaccine showed reduced sedimentation of Aβ in a brain and inhibition of a cognitive function disorder. Therefore, immunization with Aβ had been appeared to be a promising method for AD treatment. However, a clinical trial of immunization of an AD patient with Aβ42 (AN1792) was dropped due to the severe side effect of excessive immunity activation. One of the reasons of this problem is appeared unintentional removal of physiological Aβ42. Therefore, it has been recognized as an essential feature to discriminate Toxic Aβ42 from physiological Aβ42 for effective inhibition of amyloid plaque formation and of progression of a cognitive function disorder in an AD patient.
A study using a solid NMR method and a systematic proline substitution method has revealed. A toxic conformer of Aβ42 having a turn structure at positions 22 and 23 and physiological conformer of Aβ42 having a turn structure at positions 25 and 26 (Non-Patent Document 1, Patent Document 1). It has also been reported that the former conformer exhibits the powerful aggregating ability and neural toxicity.